Патент USA US3038002код для вставки
United States Patent 0 3,937,992 1 C6 Patented June 5, 1962 1 2 3,037,992 an indole derivative, in which Cl, Br, I, or N02 is sub stituted in 5- and/ or 7-position, by subsequent or alterna tive treatment with a halogenating and/ or nitrating agent and subsequent action of an alkaline agent. According PROCESS FOR PREPARING OLES SUBMI TUTED IN THE BENZENE RWG . Jan Thesing and Gunther Mohr, Darmstadt, and Gunther Semler, Heppenheim an der Bergstrasse, Germany, as siguors to Rutgerswerke~Aktiengesellschait, Frankfurt am Main, Germany to a modified embodiment of the invention the indoline 2-sulfonic acid, which may be acylated, is converted by ~ No Drawing. Filed July 18, 1960, Ser. No. 43,278 Claims priority, application Germany Aug. 1, 1959 2 Claims. ((31. 260—319) This invention relates to the preparation of substitution products of indole and it has particular relation to the preparation of indoles which are substituted in the ben zene ring. , It has been known that in the indole system the hetero cyclic pyrrole ring is essentially more reactive to electro philic substitutions-eg. halogenation, nitration, sulfona tion, Friedel-Crafts reaction--than the benzene ring. treatment with S2Cl2 and subsequent treatment with an alkaline agent into 5,5’-diindolyldisul?de. If desired, the latter can be split by a conventional reducing method with 10 hydrogenation to S-mercapto-indole. Nitration of a compound of the above general Formula I, can be carried out according to methods which are con ventional in aromatic substitutions, e.g. by the action of .a nitrating acid mixture. Thereby, ?rst a mixture of the 5- and 7-substitution product is obtained, which can be separated eg by distillation with steam. Under suitable reaction conditions-—-e.g. extended period of treatment or increased concentration of the nitrating acid—the 5,7-di Therefore, in carrying out these substitutions a reaction nitro-compound can also be prepared. of the substituent in the pyrrole ring can be generally 20 By the action of acetyl nitrate on compounds of the observed. For this reason the preparation of indoles sub above general Formula I, in a smooth reaction a nitro stituted in the benzene ring could be performed by indirect derivative substituted exclusively in the 7-position can be methods only. obtained and the resulting product can be converted by It has been hitherto necessary either to use as starting subsequent treatment with alkali into 7-nitro-indole. This material a phenyl hydrazone substituted in the nucleus, reaction can be carried out, for example in acetic anhy which was subjected to indole synthesis according to dride as the solvent. Fischer, or indole was hydrogenated to indoline, which Furthermore, a salt of N-acyl-indoline-Z-sulfonic acid, was then subjected to the desired substitution and the sub ‘which is already halogenated or nitrated in the 5-position, stituted indoline was then dehydrogenated to the corre can be subjected to a subsequent nitration or halogenation. sponding indole compound. The preparation of the sub E23 O In proceeding in this manner, in both cases a disubsti stituted phenyl hydrazone as well as the procedure calling ' tuted indole derivative is obtained, which is differently sub for hydrogenation and dehydrogenation, are relatively troublesome and the yields of these procedures are unsatis factory. Moreover, said ?rst mentioned method is not stituted (halogenated and nitrated) in the 5- and 7-position. The introduction of a S-bromo substituent can be e.g. brought about by the action of elementary bromine on suitable for the preparation of indoles which are not sub- 0..‘ Cl a compound of the above Formula I. stituted in the pyrrole ring. (H. R. Snyder and C. W. Smith, J. Amer. Chem. Soc. 65, 2452 (1943).) S-iodo-indole can be prepared by the action of iodine which can be produced e.g. from potassium iodide and iodine monochloride. Chloroindoles can be prepared by reacting a compound It ‘has now been found that reactions consisting of sub stitutions in the benzene ring of the indole system can be of the above Formula I with chlorine water, or an alkali carried out if the aromatic character of the pyrrole ring 40 hypochlorite, or with chlorine in glacial acetic acid. in the indole molecule is temporarily canceled by the Thereby a mixture of chloro-indole derivatives substituted formation of an indole-2-sulfonic acid (hydrogen suliite by chlorine in the 5- and/ or 7-position are formed, which compound of indole). A sulfonic acid salt of indoline can be subsequently separated into the individual compo- _ reacts in the substitution reactions like an o-substituted nents of the mixture. derivative of aniline. The amino~group of the indole ring 45 Splitting oil‘ of the acyl group protecting the amino is preferably blocked according to conventional methods, group and of the hydrogen sul?te is preferably carried out for example by acylation. According to the present invention, it is possible to sub stitute an indoline-Z-sulfonic acid salt of the Formula I by treatment with an alkaline agent in one reaction step. For example, concentrated potassium hydroxide or con centrated sodium hydroxide, is suitable for this reaction. The indoles substituted in the benzene ring according to the present invention can be utilized for the preparation of further indole derivatives. For example, by the re duction of the nitro-group S-amino indole and from the latter derivatives N-substituted in the amino-group can be l R (I) 55 prepared, according to conventional methods. From com pounds which correspond to the above Formula I and are wherein R stands for H or acyl and Me is a metal ion, halogenated in the 5-position, S-cyan-indole can be easily preferably Na or K, by halogenating and/ or nitrating in obtained. ' the para and/ or ortho-position to the amino group. Sub The salts of indoline-Z-sulfonic acid used as starting sequently, by treatment with an alkaline agent the hydro 60 materials are easily obtainable. For example, the alkali gen snl?te and, if desired, simultaneously the protecting salts can be obtained by reacting indole with alkali hydro acyl group can be split off. In this manner, indoles sub gen sul?te. stituted by Cl, Br, I and/or N02 in 5 and/or 7 position The N~acyl-indoline-sulfonic acid salts are obtained can be obtained in a simple manner. Furthermore, by from the corresponding indoline-Z-sulfonic acid salts by treatment of a compound of the Formula I with S2Cl2 65 conventional acylation methods. Examples of the latter and subsequently with an alkaline agent, 5,5’ di-indolyldi are the conventional reactions with acetic anhydride, acetyl sul?de and by reduction of the latter S-rnercapto-indol can chloride, benzoyl chloride, p-toluene sulfonic acid chloride be prepared. and with similar compounds. The N-acyl residues can be Thus, the present invention relates to a process for pre later easily removed by simple treatment with alkali ac paring indoles substituted in the benzene ring. In this cording to conventional methods. process a salt, preferably an alkali salt, of an indoline-Z The compounds prepared according to the present in sulfonic acid, which may be N-acylated, is converted into ' vention can be used not only as starting material for fur . sogMe 3,037,992 '32. pended in one liter of water and distilled with steam. The ther derivatives of indole but they are also important , distillate thus obtained is repeatedly extracted with ether and therether solution is evaporated after drying over so intermediate products for the preparation of pharmaceutic substances. 7 . dium sulfate. The residue yields, after being subjected EXAMPLE 1 (a) Preparation of the sodium salt of indoline-Z-sul U! to chromatography in a column of aluminium oxide, by elution with a benZene-cyclohexane mixture (2:1) 7-nitro indole in the form of yellow needles having a melting point ionic acid.—50 grams of indole are dissolved in 70 com. of ether and shaken with a mixture of 150 ccm. of com of. 94°—97° C. The still hot residue of the steam distilla tion is sucked o?. From the ?ltrate upon cooling the of water and 300 ccm. of alcohol of 96%, for 10 hours. 10 S-nitro-indole crystallizes in almost pure form. It is sep The colorless crystals are separated by suction, Washed arated by ?ltration and dried. A further amount of S-ni mercial soduim hydrogen sul?te solution ‘of 40%, 50 ccm. with methanol and ether and dried. (b) Preparation of the sodium. salt of N-acezyl-in - tro-indole can be recovered by boiling with water the residue found on the suction ?lter. By recrystallizing the doline-Z-sulfonic acid-15 grams of the sodium salt of in doline-Z-sulfonic acid, 15 grams of sodium hydrogen sul ?te and 150 ccm. of acetic acid anhydride are subjected to fast stirring at 50° C. After about 1/2 hour the mixture starts to swell. After a total period of 3 hours the prod S-nitro-indole from benzene-cyclohexane, yellow needles having a melting point of l40°~l41° C. are obtained. As examples of the. various uses of products prepared according to the present invention the following may be mentioned: 5-bromoindole can be used as an interme not is sucked off and can be used in crude condition in the ' subsequent reactions. 7 (0) Preparation .of 5-bromo-indole.-Sodium salt of N-acetyl-indoline-Z-sulfonic acid freshly prepared from diate product in the preparation of harmane (see I. Am. 20 Chem. Soc, vol. 70, page 225 (1948)); 7-nitroindole can 10 grams of sodium salt of indoline-Z-sulfonic acid, is dis I solved under cooling and stirring in 50 ccm. of water and be used for preventing the growth of a lactobacillus (see J. Organic Chemistry,ivol. 22, page 84 (1957) ); S-chloro indole and 7-chloroindole can be used for biological in vestigations (see J. Chem. ‘Soc. 1955, page 3501). separated from undissolved material by ?ltration. In the 25 It will be understood from the above that this inven tion is not limited to the speci?c substances, steps, propor dropwise at 0°—5° C. into the solution. Subsequently, the tions and other conditions and procedures speci?cally de reaction mixture is stirred at 0° C. for one hour, stirred scribed above and can be carried out with various modi at room temperature for a further hour, diluted with 200 ?cations. For example, while Me stands preferably for course of 1 hour- 15 grams of bromine are introduced com. of water and the clear solution is rendered alkaline oif and washed with water. After recrystallization from alcohol of 30-40%, or after puri?cation by steam distil lation, colorless needles having a melting point of Na or K, it may also stand for other metal ions, such as NH4, ‘Ca, or a heavy metal. These and other modi?ca tions may be made without departing from the scope of the invention as de?ned in the appended claims. What is claimed is: 1. In a process for preparing chloro-, bromo-, ionic 90°—9'1° C. are obtained. and nitro-derivatives of indole, which contain in the ben at 20°-—30° C. with sodium hydroxide solution of 20%. ' After standing over night the crystals formed are sucked EXAMPLE 2 Preparation‘ of 5—i0‘d0-ind0le.--80 grams of the sodium zene ring of the indole molecule a substituent selected from the group consisting of Cl, Br, ‘I, and --NO2 in a position selected from the group consisting of 5 and 7 salt of indoline-Z-sulfonic acid are acetylated in the man ner described in the above Example 1(1)). The sodium 40 positions (a) the step of mixing indole in solution with Mel-I803 in order to form a, compound of the formula salt of N-acetyl-indoline-2-sulfonic acid is dissolved under cooling in 300 ccm. of water'and ?ltered. Subsequently 40 grams of potassium iodide are added and during 10 minutes 40 ccm. of iodine monochloride are dropwise sea-Me‘: added at 0°-4° C. The mixture is then stirred for one 45 N hour under cooling with ice, and then stirred for an addi lit tional hour at room temperature, 1500 ccm. of water are added, the precipitate formed is separated by ?ltration and in which Me stands for a cation selected from the group the ?ltrate is rendered alkaline with concentrated sodium consisting of Na, K, NH; and Ca; (b) mixing this com— hydroxide solution at 20° C. After standing over night 50 pound with an N-acylating agent selected from the group the precipitate formed is sucked off, washed with water, consisting of acetyl- benzoyl- and p-toluene sulfonic acid and dried. ' Needles of a weak yellow color are obtained, radicals in order to block ‘the amine group of the indole; which are puri?ed by re-precipitation with water from (c) reacting the compound resulting in (b) with the sub ethanol solution and have then a melting point of stituent to be introduced into positions selected from the 99400“ C. ' 55 above de?ned group; and (d) subjecting the resulting sub stitution product to treatment with an alkali hydroxide EXAMPLE 3 in order to split ed the acyl group and the hydrogen sul Preparation of 5- and 7-nilr0 ind0le.-—-The sodium salt. ?te to form a product of the formula of N-acetyl-indoline-2-sulfonic acid prepared from 15 grams of the sodium salt of indoline-Z-sulfonic, acid in the manner described above, is disoslved under good cool 60 ing and with stirring in 200 ccm. of water. To the ?l xi-il tered solution at 0°—5° C. a cold mixture of 50 ccm. of nitric acid of 65% with 50 ccm. of concentrated sulfuric acid are dropwise added within 30 minutes. The tempera ture should thereby remain below 0° C. Subsequently, the reaction mixture is stirred for one hour at 0° C. and for an additional hour at room temperature, then diluted with 150 ccm. of water and rendered alkaline with con centrated sodium hydroxide solution under cooling below 40° C. At a change point the previously light-brown solu 70 tion suddenly becomes dark-brown and yellow crystals start to seperate. After standing over night the crystals . N wherein X is selected from the group of substituents de ?ned above. 2. A process as claimed in claim 1, in which Me stands for the sodium ion and the acetyl-radical is used as the N-acylating agent. 7 References Cited in the ?le of this patent Gall et al.: I. Organic Chem, vol. 20, pages 1538-1544 (1955). are sucked off and washed with a small quantity of cold Tomino: J. Pharm. Society (Japan), vol. 77, pages water. The precipitate consists of a mixture of S-nitro indole with 7-nitro-indole. The still wet mixture is sus 75 1087-1093 (1957).